Introduction: Lung cancer is the major cause of cancer-related deaths in United States and lung adenocarcinoma (LUAD) is its most common subtype exhibiting highly variable molecular signature. Identification of patients at high risk of developing invasive tumor is important for their better management.

Experimental procedure: We obtained 53 early-stage LUAD patient's tumor samples, histopathologically classified into 32 indolent (adenocarcinoma in situ, minimally invasive and lepidic predominant adenocarcinoma) and 21 invasive (acinar predominant, papillary predominant, micropapillary predominant and solid predominant adenocarcinoma) subtypes and profiled their transcriptomes by RNA sequencing. We clustered these samples in an unsupervised manner followed by additional supervised clustering into 2 groups.

Using our signature genes, we categorized 51 lung adenocarcinoma cell lines from Cancer Cell Line Encyclopedia database based on their relative invasiveness scores derived from elastic network trained in our dataset. We chose NCI-H1792, NCI-H1373, SK-LU-1 and NCI-H2009 representing high while HCC1833, Calu3 and NCI-H3255 representing low invasive signature for our in vitro functional assays.

Summary: Our clustering significantly overlapped with the groups classified by histology and we defined 21 tumors as “invasive” and 32 as “non-invasive” early stage LUAD. We identified 1,322 differentially expressed genes between two groups with 526 upregulated and 796 downregulated genes in invasive tumors. Among the enriched signature genes, AURKA and AURKB were significantly upregulated in the “invasive” group. We used two potent aurora kinase inhibitors AMG 900 and PF-03814735 to determine the effect of aurora kinase inhibition on invasiveness of LUAD cells. AMG 900 and PF-03814735 significantly inhibited Aurora kinase (Aur-) A and B activity, but did not affect cell viability (IC50 ≥2μM) of all cell lines regardless of their invasiveness score. Of note, both drugs significantly suppressed wound healing, migration and invasion of all four “invasive” cell lines at much lower 100nM. Moreover, the cells with low invasive signature used in the study showed little migration and invasion thus confirming the validity of our elastic network analysis for their relative invasiveness.

Conclusion: Here, we have identified a robust gene signature that distinguishes invasive to indolent non-invasive early-stage LUADs, which may lead to development of assays on clinical specimens such as biopsy to identify patients at high risk of developing invasive LUAD at an early stage. This gene signature also suggests Aur-A and B promote invasiveness in early stage LUAD. Our in vitro functional data suggest that targeting Aur-A and B could be a promising approach for management of early stage LUAD patients who are more likely to develop an invasive tumor.

Citation Format: Abhilasha Sinha, Seungyeul Yoo, Hideo Watanabe, Jun Zhu, Charles A. Powell. Aurora kinase: A target modulating invasiveness of lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 814.